1. Field of the Invention
The present invention is broadly directed to a method for inhibiting endothelial cell growth and capillary permeability associated with vascular endothelial growth factor (VEGF), e.g., the increased cell growth and permeability induced by (VEGF) using an inhibitor of the .beta. isozyme of Protein Kinase C (PKC). This VEGF induced condition is closely associated with neoplasia in mammals and other disorders including pulmonary edema.
The present invention is particularly directed to the use of an inhibitor of the .beta. isozyme of Protein Kinase C (PKC) for treating neoplastic diseases including capillary hemangioblastomia, breast cancer, Kaposi's sarcoma, glioblastoma, angiomatous disorders, colorectal cancer, medulloblastoma, gastric carcinoma, adenocarcinomas of the gastrointerestinal tract, malignant melanoma, ovarian cancer, non small cell lung cancer, prostate cancer, malignant effusions, preitumoral edema, e.g., intracerebral edema and cysts associated with brain tumor, bladder carcinoma, von Hippel Lindau Syndrome, renal cell carcinoma, skin cancer, thyroid malignancies, cervical cancer, hepatocellular carcinoma, rhabdomyosarcoma, and leiomysarcoma and certain other VEGF related disorders as described herein.
2. Description of Related Art
VPF/VEGF is a glycosylated, multifunctional cytokine. Over-expression of VPF/VEGF is associated with neoplasia, and several other disease conditions.
VPF/VEGF induces endothelial cell proliferation, excessive permeability via activation of vesicular-vacuolar organelle mediated transport, migration and actin reorganization with shape changes and ruffling. It alters endothelial cell gene expression, inducing increased production of tissue factor and several proteases, including interstitial collagenase and both the urokinase-like and tissue plasminogen activators. The majority of these same genes are induced by phorbol myristate acetate (PMA) stimulated activation of PKC.
VPF/VEGF is abundantly expressed and secreted by most human and animal tumors examined thus far. VPF/VEGF may directly affect tumor cells, e.g., tumor cells of glioblastoma, as well as play an important role in the induction of tumor angiogenesis (Claffey, et al., Cancer Research 56, 172-181 (1996) and the references cited therein).
The angiogenic potential of VEGF likely is enhanced by the synergistic activity of fibroblast growth factor liberated by cellular disruption or death. (Pepper, et al., Biochem Biophys Res. Commun., 189:824-831 (1992); Muthukrishnan, et al., J. Cell Physiol., 148:1-16 (1991)).
Tumor growth and metastasis are closely related to enhanced VEGF expression. A chemical signal from tumor cells can shift resting endothelial cells into a phase of rapid growth. Of the twelve known angiogenic proteins, those most commonly found in tumors appear to be basic fibroblast growth factor (bFGF) and vascular endothelial growth factor (VEGF), also known as vascular permeability factor (VPF) (Folkman, J. New England J. of Medicine., Vol 999 (26): 1757-1763(1995) and the references cited therein).
The realization that tumor growth requires new blood vessels and the identification of chemical factors that mediate neovascularization or angiogenesis have broadened the understanding of pathologic processes and opened new avenues to the treatment of these diseases. Nine different inhibitors of angiogenesis are currently being studied in phase 1 or 2 clinical trials as treatment for a wide spectrum of solid tumors, including breast, colon, lung, and prostate cancer as well as Kaposi's sarcoma. (Folkman, J. Tumor angiogenesis In Mendelsohn J. Howley P M, Israel M A. Liotta L A. eds. The Molecular Basis of Cancer, Philadelphia: W. B. Saunders. 1995:206-232) One of these drugs, TNP-170, a synthetic analogue of fumagillin (Denekamp J. Br J Radiol 66:181-196,1993) has been approved by the FDA for phase 1 testing in many patients with solid tumors. Other inhibitors of angiogenesis currently in clinical trials in patients with advanced cancer include platelet factor 4; carboxyaminotriazole; BB-94 and BB-2516; metalloproteinase inhibitors; the sulfated polysaccharide tecogalan (DS-152); thalidomide; interleukin-12; and linomide. (Flier et al., The New England Journal of Medicine, vol 333 pp1757-1763, 1995 and the references cited therein)
PKC inhibitors also have been proposed for cancer therapy, see U.S. Pat. No. 5,552,396. However, the effectiveness of the inhibitors of the .beta. isozyme of PKC against particular neoplastic diseases was not known. Given the role VEGF plays in certain neoplastic and other diseases, there is a need in the art to identify additional drugs that are specifically targeted at the function of VEGF.